Heart valve disease represents a major cardiovascular disease worldwide. Besides acquired heart disease, also congenital heart disease (affecting 1% of all life births) is responsible for a major disease global load. Currently used heart valve replacement constructs are fabricated from either metallic or fixed “biological” materials. The metal-based “mechanoprostheses” are prone to thromboembolic complications and lack growth-adaptive capacities (Schoen, 2008). While bioprosthetic materials, e.g. fabricated from glutaraldehyde-“fixed” xenogenic or homogenic native tissues, are not associated with an increased risk of clotting activation, they are still limited by the lack of growth-adaptive capacities of these implants. Particularly in pediatric patients this is of major concern, as the valvular annulus undergoes rapid changes throughout the physiological development and growth of the young patients. This implies that these young patients currently have to undergo repeated reoperations causing increased morbidity and mortality (Talwar et al., 2012). This aspect of growth has been addressed by a plethora of studies and investigations throughout the last 20 years. In particular, the field of cardiovascular tissue engineering has shown gradual success also demonstrating “growth-adaptation” in studies by independent groups focusing on tissue engineered arteries (Hoerstrup et al., 2006; Brennan et al., 2008).
However, while for tissue engineered arteries adequate function (and growth adaptation) could be demonstrated and the technology has also entered first-in-man clinical trials in Japan (Hibino et al., 2010) and the US (Vogel et al., 2011; Dolgin et al., 2011), the development of tissue engineered heart valves is experiencing obstacles partly derived from the complexity of the physiological environment of heart valves (Weber et al., 2011; Schmidt et al., 2010).
In particular, the radial leaflet shortening observed in ovine and non-human primate preclinical animal models is of major concern (Weber et al., 2011; Schmidt et al., 2010). Therefore, so far no tissue engineered heart valve has entered routine clinical practice, and therapy for patients with heart valve disease remains to be highly limited. However, a growth-adaptive heart valve replacement is of very high interest as the bioengineered valves would meet an even much higher medical need than in the case of vascular grafts (Vogel et al., 2011; Dolgin et al., 2011).
WO 2009/108355 A1 discloses a bioprosthetic heart valve replacement comprising a tubular segment that has a longitudinal strip of material forming a loop created by two releasable seams. When it becomes necessary to increase the lumen, the seams are broken or irreversibly deformed by the application of a radial force, such as by a balloon expandable member. US 2003/065386 A1 describes a radially expandable endoprothesis device which is constituted of a combination of superelastic alloys and bioresorbable materials. Another radially expandable heart valve is disclosed in WO 2012/018779 A2; it is based on a frame with rigid support elements that are slidingly connected to each other and thereby allow for an increase in diameter.
U.S. Pat. No. 5,383,926 A describes a re-expandable endoprothesis device formed by an elongated sleeve member having a longitudinal lateral slot, the edges of which are initially connected by expansion limiting means formed as strips disposed across the lateral slot. The device can be brought—by means of a balloon catheter—from an non-expanded configuration to a first expanded configuration, the latter being defined by the expansion limiting strips. By breaking or removing the strips, the device can be expanded further to a second expanded configuration, which is basically not limited by any restraining means. Only two specific embodiments of this second expansion step are described: breaking of the strips by reinsertion of the ballon catheter, or biodegration of the strips, in which case the sleeve needs to provide an inherent spring action driving the sleeve walls in radially outward direction.
US 2013/030521 A1 discloses a device for regulating blood pressure between a patient's left atrium and right atrium and comprising an hourglass-shaped stent region. In some embodiments the device includes one or more biodegradable components that increase the cross-sectional area of the device so as to compensate for tissue ingrowth. This is achieved in two possible ways: either by having a layer of biodegradable substance on the inner surface. Alternatively, a small-diameter constriction may be initially provided by sewing with a biodegradable thread, dissolution of which will lead to an opening up of the constriction.
US 2006/253188 A1 and US 2011/066237 A1 disclose prosthetic tissue valves which, in an unstressed position, are substantially planar and flat. They are generally configured to have a larger diameter than the inner diameter of an annulus in a defective valve to be replaced. For implantation the valve is brought into a folded, biased configuration that exerts a pressure in radially outward direction.
Accordingly, it is an object of the present invention to provide an improved biological heart valve replacement for pediatric patients that does not have the above mentioned shortcomings. In particular, the biological heart valve replacement of the present invention does not need insertion of a balloon catheter for being expanded, nor does it need to be provided with an inherent elastic force directed in radially outward direction. Another object of the present invention is to provide a method of manufacturing a biological heart valve replacement according to the invention.